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Chimeric antigen receptors designed to overcome transforming growth factor-?-mediated repression in the adoptive T-cell therapy of solid tumors.

ABSTRACT: Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells produced lasting remissions in the treatment of advanced, so far refractory B-cell malignancies; however, the elimination of solid tumors remains so far elusive. The low efficacy of CAR T cells is thought to be due to the immune-repressive milieu within the tumor lesion, predominantly mediated by transforming growth factor-? (TGF-?) that represses effector T-cell activities and drives differentiation towards regulatory T cells (Tregs). Seeking to boost antitumor immunity, TGF-? is currently targeted by different means in pre-clinical studies. While a recent clinical trial showed the utility of shielding CAR T cells from TGF-? repression, further strategies in counteracting TGF-? in the adoptive cell therapy warrant exploration. We here discuss the most recent advances in the field and draw future developments to make CAR T-cell therapy more potent in the treatment of solid cancer.

SUBMITTER: Hartley J

PROVIDER: S-EPMC6589154 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Chimeric antigen receptors designed to overcome transforming growth factor-β-mediated repression in the adoptive T-cell therapy of solid tumors.

Hartley Jordan J Abken Hinrich H

Clinical & translational immunology 20190622 6

Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells produced lasting remissions in the treatment of advanced, so far refractory B-cell malignancies; however, the elimination of solid tumors remains so far elusive. The low efficacy of CAR T cells is thought to be due to the immune-repressive milieu within the tumor lesion, predominantly mediated by transforming growth factor-β (TGF-β) that represses effector T-cell activities and drives differentiation towards regulatory ...[more]

PMID: 31236274

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Project description:BackgroundImmunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy.MethodsWe developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy.ResultsHLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter.ConclusionsOur novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.

Dataset Information

Chimeric antigen receptors designed to overcome transforming growth factor-?-mediated repression in the adoptive T-cell therapy of solid tumors.

Publications

Chimeric antigen receptors designed to overcome transforming growth factor-β-mediated repression in the adoptive T-cell therapy of solid tumors.

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